rs267607170

Variant names:

• chr3-10149814-A-G
• rs267607170
• NM_000551.4:c.491A>G
• VHL p.Gln164Arg

Your query was ambiguous. Multiple possible variants found:

• chr3-10149814-A-G
• chr3-10149814-A-T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):​c.491A>G​(p.Gln164Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000697523: experimental evidence evaluating an impact on protein function, and demonstrated that while this variant didn't affect elongin B and C binding in an in vitro peptide-binding assay, the Q164R mutant full-length protein had reduced binding ability to elongin B and Cul2 in transiently transfected renal carcinoma cells (Ohh_1999). Another study also reported that though the variant protein had retained elongin C binding, the variant significantly reduced the intracellular stability of VHL protein (Park_2015)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q164E) has been classified as Likely pathogenic. The gene VHL is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.26
• Publications: 13 publications found

Genes affected

VHL (HGNC:12687): (von Hippel-Lindau tumor suppressor) This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]

VHL Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000287086 (HGNC:):

ACMG classification

Specifications for VHL are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000697523: experimental evidence evaluating an impact on protein function, and demonstrated that while this variant didn't affect elongin B and C binding in an in vitro peptide-binding assay, the Q164R mutant full-length protein had reduced binding ability to elongin B and Cul2 in transiently transfected renal carcinoma cells (Ohh_1999). Another study also reported that though the variant protein had retained elongin C binding, the variant significantly reduced the intracellular stability of VHL protein (Park_2015).; SCV001185112: In vitro functional studies do not show specific impaired functions, including elongin C binding, however, one study showed a shorter protein half-life than wild type leading the authors to speculate that the protein may be unstable (Ohh M et al. J. Clin. Invest. 1999 Dec;104:1583-91; Maynard MA et al. J. Biol. Chem. 2003 Mar;278:11032-40; Park KS et al. BMC Cancer. 2015 Oct;15:800).
• PM1: In a hotspot region, there are 33 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 18 uncertain in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-10149813-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 625253.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 3-10149814-A-G is Pathogenic according to our data. Variant chr3-10149814-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.491A>G	p.Gln164Arg	missense	Exon 3 of 3	NP_000542.1	A0A024R2F2
	VHL	NM_198156.3		c.368A>G	p.Gln123Arg	missense	Exon 2 of 2	NP_937799.1	A0A0S2Z4K1
	VHL	NM_001354723.2		c.*45A>G		3_prime_UTR	Exon 3 of 3	NP_001341652.1	A0A8Q3WL21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.491A>G	p.Gln164Arg	missense	Exon 3 of 3	ENSP00000256474.3	P40337-1
	VHL	ENST00000345392.3	TSL:1	c.368A>G	p.Gln123Arg	missense	Exon 2 of 2	ENSP00000344757.2	P40337-2
	VHL	ENST00000477538.2	TSL:1	n.1371A>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000258 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Von Hippel-Lindau syndrome (3)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.16	T
Varity_R		0.95
gMVP		0.90
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs267607170;

hg19: chr3-10191498;